Paroxetine-induced transient apoptosis and delayed neurogenesis act on social behavior in developing zebrafish

Autism spectrum disorder (ASD) is a neurodevelopmental condition caused by various genetic and environmental factors. This disorder has the cardinal symptoms including impaired social behavior involving the amygdala. Ingesting antidepressants such as paroxetine in early pregnancy increases the risk of ASD in offspring. However, a comprehensive picture of the underlying pathogenic mechanisms remains elusive. Here we demonstrate that early exposure of zebrafish embryos to paroxetine retards neurogenesis in the optic tectum and the telencephalon that includes a region corresponding to the mammalian amygdala. Paroxetine-treated embryos exhibit impaired growth, with small heads and short body lengths resulting from transient apoptosis. This is reminiscent of the early-onset fetal growth restriction (FGR) associated with ASD. Interestingly, the delayed neurogenesis in the small heads was found to be restored after the cessation of paroxetine. This restoration was accompanied by extended retinotectal projections, suggesting brain-preferential remodeling. Finally, social behavior of the paroxetine-treated fish was examined. Our findings imply a biological mechanism underlying early exposure to paroxetine, a risk factor associated with the pathogenesis of ASD.